The long-term objective of this research program is to identify and study principles of organization in vertebrate central nervous system synaptic circuits. Of particular interest is how fundamental aspects of organization in local circuits subserve the parcellation of the nervous system into functional domains. Local circuits are defined as those whose synaptic connections are restricted to a given region of the nervous system. During the previous period of support this laboratory developed the olfactory system as an ideal model system for studying principles of local circuit specification. The current proposal seeks to build on this body of knowledge to address new and controversial hypotheses about local circuit organization. Specifically, to test the hypotheses that: 1) the pattern of innervation of the olfactory bulb glomeruli by primary afferents underlies a subglomerular level of organization; 2) the convergence of olfactory nerve synapses is higher onto projection neurons than onto glomerular layer interneurons; 3) that glomerular dendrodendritic circuits subserve intraglomerular lateral inhibitory networks; and 4) that centrifugal afferents to the glomerular layer differentially influence local circuit function. The techniques employed will include fight microscopy, 1OOk transmission electron microscopy, 1000kV high voltage electron microscopy, immunohistochemistry and the selective impregnation of subpopulations of neurons with markers such as horseradish peroxidase, silver or gold. The results will be important for understanding the fundamental organization of the olfactory system and how odors are processed. These results will generalize to other regions of the nervous system where local circuit organization underlies the parcellation into functional domains. Also, with the recognition of early involvement of the olfactory system in Alzheimer's Disease the results will be important for understanding the basic etiology and spread of dementia. Finally, in view of the low threshold for seizure activity and the demonstrable involvement of olfactory system structures in human temporal lobe epilepsy, the results will be important in understanding how the organization of synaptic circuits may contribute to epileptiform diseases.